Bioadhesive gel based on hydroxyethycellulose

ABSTRACT

Disclosed are compositions in the form of a bioadhesive gel that adheres to the mucous membranes, in particular the vaginal mucosa, for the application of active ingredients and/or principles, comprising hydroxyethylcellulose as the only gelling agent.

This invention relates to compositions in the form of a bioadhesive gelthat adheres to the mucous membranes, in particular the vaginal mucosa,for the application of active ingredients and/or principles.

Bioadhesion is the property whereby some hydrogels adhere to biologicaltissues, in particular to mucous-coated epithelia such as the gastric,buccal, vaginal and rectal mucosae.

This property has been exploited to develop drug delivery systems,especially in order to increase the time over which drugs remain incontact with certain sites or areas of therapeutic interest, giving riseto systemic effects (thus increasing transmucosal absorption) or localeffects.

The most commonly used polymers that are capable of forming hydrogelsand imparting bio- and/or muco-adhesion are acrylic or methacrylic acidpolymers, possibly cross-linked, and chitosan, or its derivatives.

In particular, for drugs designed for gynaecological use, a bioadhesivegel able to ensure prolonged contact between the active ingredient andthe vaginal mucosa, and gradual release of that ingredient over time,provides the ideal solution in terms of efficacy and compliance bypatients.

Bioadhesive vaginal gels have consequently been disclosed, for example,in U.S. Pat. No. 6,159,491, US 2002012674, US 2003091642, WO 200047144,WO 200203896, WO 200143720 and WO 9610989. In all these cases, anacrylic acid polymer (Carbomer or polycarbophil) is used asviscosity-controlling or bioadhesive agent.

WO 200015192 describes mucoadhesive formulations in which chitosan isused instead of the acrylic acid polymer.

However, the problem of obtaining a bioadhesive formulation thatpresents the following advantages and properties:

-   -   release of drug for up to approximately 24 hours;    -   absence of gelling/bioadhesive agents, characterised by the        presence of acid groups, which are therefore sensitive to the        ionic strength of the medium, and sometimes need to be        neutralised with bases;    -   the possibility of carrying drugs with different        chemico-physical properties, in particular water-soluble drugs        and lipophilic drugs which are substantially insoluble in water;    -   reduction of the time and cost of the treatment remains        substantially unsolved.

It has now been found that said objectives can be achieved bybioadhesive gel formulations that adhere to the mucous membranes, inparticular the vaginal mucosa, comprising hydroxyethylcellulose as theonly bioadhesive polymer. This gelling excipient has no acid groups andis therefore not dependent on the ionic strength of the medium; it alsohas a matrix effect which allows particularly slow, gradual release ofthe active ingredient, for up to 24 hours.

This invention therefore relates to compositions in the form of anaqueous gel for the intravaginal delivery of active ingredients,comprising hydroxyethylcellulose as the only gelling and bioadhesiveagent.

The compositions of the invention may also contain glycerol, diethyleneglycol monoethyl ether, surfactants, preservatives, acidifiers and otherexcipients in common use for the form of delivery considered herein.

The compositions of the invention will preferably contain 1 to 5% byweight of hydroxyethylcellulose, 25 to 90% by weight of water, 5 to 25%by weight of glycerol, 5 to 50% by weight of diethylene glycol monoethylether, 0.01 to 10% by weight of surfactants, 0.05 to 1% by weight ofpreservatives, and 0.01 to 1% by weight of acidifiers.

Preferably, the hydroxyethylcellulose content is higher than 2% and lessthan 4%.

Hydroxyethylcellulose is commercially available from many sources: it ispreferred an hydroxyethylcellulose having a degree of substitution ofabout 1.5 (corresponding to 3 hydroxyethyl groups every two saccharideunits) and a molecular weight estimated from intrinsic viscositymeasurements ranging from 1.0 to 1.3×10⁶. Hydroxyethylcellulose havingsaid characteristic is available under the trade-mark Natrosol 250 HX byHercules Inc. UK.

The percentage of active ingredient will obviously depend on thecharacteristics of the selected drug, and may vary within a wide range,for example from 0.01 to 10% by weight.

Active ingredients which can be advantageously formulated according tothe invention include antifungals, antiseptics and antimicrobials,antibiotics, analgesics, local anaesthetics, antihistamines,anti-inflammatory agents, contraceptives, hormones, and combinationsthereof.

Examples of these active ingredients include, in particular, econazole,miconazole, fluconazole, ciclopiroxolamine, nifuratel, nystatin,chlorhexidine, ibuprofen, ketoprofen, naproxen, benzydamine,benzalkonium chloride or other quaternary ammonium antiseptics,nonoxynol-9 and all other active ingredients of interest forgynaecological applications.

The following examples illustrate the invention in greater detail.

EXAMPLE 1

Composition Percentage Purified water 81.9% Glycerol 12.9% Chlorhexidinedigluconate, 20% solution w/v 2.7% Hydroxyethylcellulose (Natrosol 250HX) 2.5%

EXAMPLE 2 Ibuprofen Vaginal Gel

Composition Percentage Ibuprofen 0.100% Benzalkonium chloride 0.150%Polyoxyethyen-20-monocetyl ether (Brij 58) 0.500% Hydroxyethylcellulose(Natrosol 250 HX) 2.500% Diethylene glycol monoethyl ester (TranscutolP) 10.000% Purified water 86.750%

EXAMPLE 3 Econazole Nitrate Vaginal Gel

Composition Percentage Econazole nitrate 1.000% Benzalkonium chloride0.150% Hydroxyethylcellulose (Natrosol 250 HX) 2.500% Polysorbate 80(Tween 80) 4.000% Glycerol 10.000% Diethylene glycol monoethyl ester(Transcutol P) 40.000% Purified water 42.350%

EXAMPLE 4 Study Of Bioadhesion Of Vaginal Gels

Bioadhesion was measured in vitro using a suitably modified Lloyddynamometer. The measurement substrate (rabbit gastric mucosa orpolypropylene) was fixed with an adhesive to the upper support, which inturn was connected to the mobile crossbar, and 200 mg of the testformulation were placed on the lower support so as to cover the surfaceevenly. After effecting close contact between the formulation and thesubstrate (30 s), the crossbar was raised at a defined, constant speeduntil the two surfaces separated.

A 20 N load cell was used for the measurements [J. Y. Chang, Y-K. Oh, H.S. Kong, E. J. Kim et al., J. Control. Release 82 (2002) 39-50; S.Skulason, T. Kristmundsdottir, W. P. Holbrook, Bio-GelsPharmaceuticals].

Five measurements were taken for each sample; the parameters consideredwere the maximum breaking load (ML) and the adhesion work (W).

The operating conditions used in the study are reported below. ApparatusLloyd LRX Tensiometer Equipped with clamps for adhesion tests Testconditions Crossbar speed 0.1 mm/s Load cell 20 N Contact time betweensubstrate and gel 30 s Contact surface rabbit gastric mucosa/polypropylene

Results

The results are shown in Table 1. TABLE 1 Rabbit gastric mucosaPolypropylene FORMULATION ML (N) W (Nmm) ML (N) W (Nmm) EXAMPLE 1 0.088± 0.017 0.095 ± 0.030 0.101 ± 0.019 0.099 ± 0.014 EXAMPLE 2 0.076 ±0.012 0.069 ± 0.010 EXAMPLE 3 0.179 ± 0.032 0.155 ± 0.032

EXAMPLE 5 pH 4.0 Diffusion Test of Gels of Examples 1, 2 and 3

Diffusion medium: lactate buffer, pH 4.0

Diffusion volume: 50 mL

Temperature: 37±0.5° C.

Agitation speed: 50 rpm

Quantity of sample: 1.5 g

Release area: 4.5 cm²

Release membrane: cellulose acetate 0.45 μm.

The test for release of the drug from the gel was performed usingdiffusion cells, with cellulose acetate membranes having a 4.5 cm²surface. The quantity of gel applied was 1.5 g. At given times, anautomated system took predetermined sample aliquots, with immediate UVspectrophotometer at 254 nm.

FIG. 1 shows the diffusion profile of chlorhexidine as the mean of8±standard deviation.

FIG. 2 shows the diffusion profile of chlorhexidine from the 8 samples.

Table 2 shows the percentages released for the 8 chlorhexidine samples.TABLE 2 time sample 1 sample 2 sample 3 sample 4 sample 5 sample 6sample 7 sample 8 mean SD 0 0 0 0 0 0 0 0 0 0 0 10 12.89 8.532 11.9410.37 11.54 4.473 12.28 9.514 10.19 2.74 20 20.05 19.09 19.92 19.39 18.917.3 20.35 18.51 19.19 0.98 30 25.29 23.73 26.29 24.53 23.49 22.86 25.7324.65 24.57 1.17 40 29.94 28.16 31.35 29.54 27.11 27.24 29.5 27.47 28.791.53 60 37.63 33.33 39.02 38.09 34.48 35.99 37.73 35.43 36.46 1.97 9048.43 45.46 51.11 50.36 42.11 40.69 45.84 43.93 45.99 3.76 120 57.2553.77 59.81 60.04 49.54 51.69 53.37 51.09 54.57 4.01 150 64.1 60.1365.16 64.99 56.34 60.75 62.1 60.35 61.74 2.99 180 69.83 65.88 70.9972.06 59.42 64.05 65.88 63.19 66.41 4.31 210 75.2 72.57 76.17 79.4166.23 70.77 71.62 69.9 72.73 4.10 240 78.71 74.61 79.33 82.52 69.9 73.5274.98 73.03 75.83 4.07 270 81.79 78.38 81.54 84.88 72.61 77.04 77.8674.84 78.62 3.99 300 84.36 81.24 83.65 87.96 76.38 79.6 80.6 79.33 81.643.58

FIG. 3 shows the diffusion profile of ibuprofen as the mean of 8samples±standard deviation.

Table 3 shows the percentages released for the 8 ibuprofen samples.TABLE 3 time (min) sample 1 sample 2 sample 3 sample 4 sample 5 sample 6sample 7 sample 8 mean SD 0 0 0 0 0 0 0 0 0 0 0 30 15.56 17.83 18.9618.96 4.18 3.22 17.06 11.26 13.38 6.05 60 24.34 26.60 26.88 19.53 33.1524.14 26.71 19.95 25.16 4.06 90 30.56 28.02 32.26 28.02 34.44 36.3730.57 37.01 32.16 3.28 120 40.19 33.39 45.28 30.56 36.05 44.74 42.1639.59 38.99 4.94 150 47.26 47.54 45.56 56.60 47.63 44.74 43.77 43.7747.11 3.89 180 57.45 41.60 53.49 46.69 47.31 44.74 44.09 44.41 47.474.99 240 57.73 54.62 54.62 59.71 52.11 51.81 53.03 52.11 54.47 2.70 30068.20 61.69 59.99 63.67 68.88 61.87 69.49 62.17 64.49 3.52 360 70.1866.79 64.24 59.71 76.80 74.67 69.79 71.31 69.19 5.17 420 61.98 74.9965.65 73.30 77.41 84.72 77.71 76.50 74.03 6.73 480 78.39 72.16 71.6071.31 81.98 84.72 81.07 80.15 77.67 4.93

FIG. 4 shows the diffusion profile of econazole as the mean of 8samples±standard deviation.

Table 4 shows the percentages released of the 8 econazole samples. TABLE4 time sample 1 sample 2 sample 3 sample 4 sample 5 sample 6 sample 7sample 8 mean SD 1 8.9 8.9 10.7 11.7 9.1 8.8 10.3 12 10.1 1.3 2 12.315.5 18.4 19.1 14.4 15 17.3 19.5 16.4 2.5 3 24.1 21.6 24 25 22.1 25.321.1 23.6 23.4 1.6 4 29 26.2 28.8 30.1 30.4 28.2 25.8 32.1 28.8 2.1 534.1 30.4 32.8 34.5 36 33.4 30.2 33.7 33.1 2.0 6 40 34.2 35.4 37.6 38.436.5 34 36.3 36.6 2.1 7 40.5 36.8 37.4 39.9 41 39.2 37 38.4 38.8 1.6 844.4 39.3 38.6 41.3 43.2 40.2 39.6 41.2 41.0 2.0 9 45.2 40.6 40 43 45.842.1 42.3 44.2 42.9 2.1 10 46.1 41.8 40.9 44 47.3 44 45 45.4 44.3 2.1 1147.2 42.8 41.4 44.8 48 45.3 46.3 46.7 45.3 2.3 12 48.6 43.6 42.6 45.849.2 47.1 48.2 48.1 46.7 2.4 13 49.2 44.3 43.1 46.4 50.3 49.6 50.2 49.247.8 2.8 14 50.2 45.2 43.6 46.9 51 49.8 50.8 50.1 48.5 2.8 15 50.7 45.443.7 47.6 51.1 50 51.1 50.6 48.8 2.9 16 51.3 46 44.3 47.4 51.3 50.3 51.450.8 49.1 2.8 17 51.9 46.3 44.7 47.7 51.5 50.4 51.7 50.9 49.4 2.8 1852.6 46.3 45 47.7 51.7 50.7 51.9 51.1 49.6 2.9 19 53.1 46.8 46.7 48.2 5251.1 52 51.3 50.2 2.5 20 53.3 46.9 49.3 50.1 52.2 51.2 52.3 51.5 50.92.0 21 53.1 47 52.2 50.3 52.3 51.4 52.6 51.7 51.3 1.9 22 53.9 47.8 54.251.2 52.5 51.6 52.7 51.9 52.0 2.0 23 54.1 48.3 55.3 51.9 52.7 51.8 52.952.2 52.4 2.0 24 55.2 50.1 56.1 52 53.2 52.4 53.1 52.4 53.1 1.9

1. A composition in the form of an aqueous bioadhesive gel adapted forthe delivery of at least one of active ingredients and principles, saidcomposition comprising hydroxyethylcellulose as the only gelling agentand a bioadhesive agent, glycerol and diethylene glycol monoethyl ether,together with at least one surfactant, preservative and acidifier. 2.The composition as claimed in claim 1, comprising 1 to 5% by weight ofhydroxyethylcellulose, 25 to 90% by weight of water, 5 to 25% by weightof glycerol, 5 to 50% by weight of diethylene glycol monoethyl ether,0.01 to 10% by weight of surfactant, 0.05 to 1% by weight ofpreservative, and 0.01 to 1% weight of acidifier.
 3. The composition asclaimed in claim 1 further comprising, as an active constituent, atleast one selected from the group consisting of antifungals,antiseptics, antimicrobials, antibiotics, analgesics, localanaesthetics, antihistamines, anti-inflammatory agents, contraceptives,hormones, and combinations thereof.
 4. The composition as claimed inclaim 3, wherein the active constituent is at least one selected fromthe group consisting of econazole, miconazole, fluconazole,cyclopiroxolamine, nifuratel, nystatin, chlorhexidine, ibuprofen,ketoprofen, naproxen, benzydamine, benzalkonium chloride or otherquaternary ammonium antiseptics, and nonxynol-9. 5-6. (canceled)